Elevated plasma levels of the amino acid homocysteine increase the risk for atherosclerosis, stroke, myocardial infarction, and possibly Alzheimer’s disease. In relation to vascular biology, many studies suggest that endothelial dysfunction contributes to the complex changes that occur within the vessel wall during hyperhomocysteinemia (HHCy). The underlying molecular mechanisms that are activated during HHCy have just begun to be understood. See page 418 With regard to endothelial dysfunction, a major focus has been on mechanisms that impair NO-mediated signaling within the vessel wall (Figure). NO produced by the endothelial isoform of NO synthase (eNOS) is known to be the major endothelium-derived relaxing factor in blood vessels. Endothelium-dependent relaxation is impaired during HHCy in experimental animals and humans, in both large arteries and microvessels.1–8⇓⇓⇓⇓⇓⇓⇓ Mechanisms that mediate this impairment are very complex, as they potentially involve every major component of eNOS signaling (Figure). An intriguing mechanism now receiving increased attention involves inhibiting the activity of eNOS by increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases.9,10⇓ Schematic illustration of selected changes within the vessel wall in response to HHCy. HHCy produces decreased activity of CAT-1 (the transporter for l-arginine, the substrate for eNOS),34 increased expression of caveolin-1, an eNOS-binding protein that inhibits activity of eNOS,35,36⇓ and in some studies, reduced expression of eNOS.37 Activity of eNOS can also be inhibited by asymmetric dimethylarginine ADMA. Homocysteine increases levels of superoxide (O2−) by activating NAD(P)H oxidase and iNOS as well as by inhibiting expression and function of EC-SOD, which normally converts O2− to hydrogen peroxide (H2O2). O2− reacts extremely efficiently with NO to form ONOO−, which may oxidize tetrahydrobiopterin (BH4) and activate PARP. …